9alpha, 11beta-dichloro-17alpha-acyloxy-delta4, 6-pregnadiene-3, 20-diones and corresponding 1-dehydro derivatives



United States Patent 3,236,868 906,115 DICHLORO 17oz ACYLOXY A PREG-NADIENE-3,20-DIONES AND CORRESPONDING l-DEHYDRO DERIVATIVES AlbertBowers, Mexico City, Mexico, assignor, by mesne assignments, to SyntexCorporation, a corporation of Panama No Drawing. Filed Jan. 31, 1961,Ser. No. 85,974 Claims priority, application Mexico, Feb. 18, 1959,$3,717; Oct. 29, 1959, 56,285 12 Claims. (Cl. 260397.45)

This application is a continuationdn-part of application Serial No.9,435, filed February 18, 1960.

The present invention relates to novel cyclopentarrophenanthrenecompounds and to a novel process for the preparation thereof.

More particularly the present invention relates to 90:,113 dichloro 17aacyloxy A -pregnene-3,20-diones which may contain a halogen or methylgroup at C-6 and further unsaturation at C-1,2 and/ or C6,7.

The novel compounds of the present invention which are potentprogest'ational agents exhibiting anti-androgenie and anti-estrogenicactivity are represented by the following formulas:

Z Z on no In the above formulas X represents hydrogen, methyl, chlorine,fluorine or bromine; Z indicates a double bond or a saturated linkagebetween C-1 and C-2 and R represents an acyl group derived from ahydrocanbon carboxylic acid of less than 12 carbon atoms, saturated orunsaturated, of straight, branched, cyclic or cyclic-aliphatic chain,aromatic and may be substituted by functional groups such as hydroxy,acyloxy, alkoxy, amino, nitro or halogen. Typical ester groups are theacetate, propionate, butyrate, caproate, enanthate, trimethylaceta-te,t-butylacetate, phenoxyaceta'te, cyclopentylpropionate, aminoacetate andp-chloropropionate.

The novel compounds of the present invention unsubstituted at C-6 may beprepared by a process illustrated by the following equation:

no m3;

* CH3 CH5 5:0 {1:0 H lj l 0.33 I ib HO (IV) RIO (III) CH3 CH3 O In j iO: (V) 0: (VI) o=o '--on m or In the above equation Z and R have thesame meaning as previously set forth; Z indicates a double bond betweenC-6 and C-7 and R represents the acyl group of a hydrocarbon carboxylicacid of less than 12 carbon atoms and preferably represents the acetylgroup.

In practicing the process outlined above, A -pregnatrien-3li-ol-20-one,disclosed by A. Bowers, J. Am. Chem. Soc. 81, 4107 (1959), is acetylatedby conventional methods to form the starting compound, 3/3-acet0xy-A-pregnatrien-ZO-one (I). Upon selective epoxidation as by reaction ofthe latter compound with hydrogen peroxide under alkaline conditions,followed by reacetylation at C-3, there is formed the3B-acet'oxy-l6a,17a-oxido- A -pregnadien-2O-one (II). The oxido ring isthen opened by treatment with hydrogen bromide to afford the bromohydrin(III) in which the bromine is reductively eliminated as by refluxing thebromohydrin with Raney nickel to thus give 3,8-acetoxy-A-pregnadien-17a-ol- 20-one; the tertiary hydroxyl group is thenesterified with a hydrocarbon carboxylic acid anhydride of the typementioned previously in benzene solution and in the presence ofp-toluenesulfonic acid. The acetoxy group'at C3 is selectivelyhydrolyzed and there is formed M -pregnadien-3B,17a-diol-20-one-17acylate (IV) which upon oxidation under Oppenauer conditions istransformed into 17u-acyloxy-A -pregnadien-3,20 dione (V). Uponsubsequent reaction with a molar equivalent of chlorine in an inertsolvent such as lower aliphatic acids, as for example, acetic orpropionic acid or lower aliphatic halogenated hydrocarbon such aschloroform or carbon tetrachloride or other solvents such asdirnethylformamide o1 dimethylacetamide at a temperature between roomtemperature and 30 0, there is formed the 9u,11;8-dichloro- 17a-acylox-A-pregnene-3,20 dione (VI). Alternatively the9(1l)-dehydro-17a-acyloxyprogesterone (V) can be chlorinated bydissolving the steroid in methylene chloride and generating chlorine bythe reaction of N-chlorosuccinimide with dry hydrogen chloride, endingthe reaction at a temperature of about C.

A double bond can then be introduced at C-1,2 by refluxing the9a,1lfi-dichloro-l7a-acyloxy-progesterone (VI) with selenium dioxide ina solvent such as t-butanol in the presence of pyridine to form9a,11,8-dichloro-l7aacyloxy-A -pregnadiene-3,20-dione (VI:Z=double bond;Z=saturated linkage). For introduction of a double bond at C6,7, thelatter compound or 9u,1l/3-dichlor0-17aacyloxy-progesterone (VI) isrefluxed with a quinone such as chloranil in a mixture of ethyl acetateand acetic acid or in t-butanol to thus form 9a,1lfi-dichloro-A-pregnatrien-17ot-ol 3,20 dione acylate (VII:Z=Z=double bond) or911,11B-dichloro-A -pregnadien-17a ol 3,20- dione acylate(VII:Z=saturated linkage; Z=double bond). The last named compound can besubjected to the treatment with selenium dioxide to introduce anadditional doublebond at Cl,2 to thus form 9u,11fl-dichloro- A-pregnatrien-17u-o1-3,20-dione acylate (VII:Z=Z'=double bond) The doublebond at C1,2 can also be introduced prior to the chlorination step andmay be introduced by incubation with Corynebacterium simplex ATCC 6946or SeO as described above.

In another aspect of the present invention by first esterifying17a-hydroxy-9-dehydro-progesterone [Fried et al., J. Am. Chem. Soc. 77,1068 (1956)], followed by the addition of chlorine as described above,there may be prepared the novel compounds of the present inventionunsubstituted at C-6.

The production of the novel compounds of the present invention having ahalogen substituent at C-6 may be prepared by a process illustrated bythe following equation:

(VIII) In the above equation X represents a halogen such as fluorine,chlorine or bromine and R has the same meaning as set forth previously.

In practicing the process outlined above, A-pregnadiene-3/3,17a-diol-20-one-17 acylate (IV) is reacted with 1.1molar equivalents of a peracid such as monoperphthalic acid to form the5a,6a-oxido-A -pregnene- 3B,l7a-diol-20-one-l7-acylate (VIII). The oxidering is then opened by reaction with fiuoroboric acid as described incopending US. application 26,703, filed May 4, 1960, or dry hydrogenchloride or hydrogen bromide and the resulting halohydrin (IX) isoxidized with 8 N chromic acid followed by subsequent treatment with amineral acid to thus form the respective6a-halo-9-dehydro-17oz-acyloxyprogesterone (X). Upon reaction withchlorine as described previously there is formed the 6ozhal09u,11'3-dichloro-17a-acy1oxy-progesterone (XI).

A double bond is introduced at C1,2 by reaction with selenium dioxide orat C6,7 by reaction with chloranil as set forth above to form6u-halo-9a,1lfi-dichloro-lhacyloxy-A -pregnadiene-S,20-dione (XII) or6oc-hal09a, 1lfl-dichloro-17-acyloxy-A -pregnadiene 3,20 dione (XIII)respectively. By combining the methods of dehydrogenation there isformed 6a-hal-o-9a-,1lfi-dichlorol 7u-acyloxy-A pregnatriene-3 ,20-dione(XIV).

The preparation of the novel compounds of the present invention having amethyl group at C-6 can be illustrated by the following equation:

l\ [\O l :--orr :--OH

H0 RO (XVIII) I (XVII) OII (EH3 0' OH --OR I ,3/ i 0: O E I (XIX) I (XX)Ho CH3 (H3 OR --OR c1 ij /\j l I O1 Z N i (XXII) I (XXI) C H3 (5 H3 Inthe above equation, Z and R have the same meaning as previously setforth.

In practicing the process outlined above, 3,8-acyloxy- A-pregnadien-l7u-ol-20-one (XV) is reacted with ethylene glycol inbenzene solution in the presence of p toluenesulfonic acid to form theZO-cyclic ethylenedioxy- A -pregnadiene-3fi,17e-diol 3 acylate (XVI).The double bond at C5,6 is then selectively epoxidized by reaction with1.1 molar equivalents of monoperphthalic acid to form ethylenedioxy50,6u-0Xid0-A -pregnene- 3B,17a-diol-3-acylate (XVII). For introductionof the methyl group at C-6, the latter compound is refluxed with methylmagnesium bromide in a solvent such as benzene to form with simultaneousconversion of the acyloxy group to the hydroxyl group,6ii-methyl-20-ethylenedioxy- A -pregnene-3/3,5u,l7a-triol (XVIII). Theketal group is removed by hydrolysis as by reaction with a catalyticamount of p-toluene sulfonic acid in moist acetone at room temperatureand upon subsequent oxidation with chromic acid there is formed6fi-methyl-A -pregnene- 5a,17a-di0l3,20-dl0n (XIX) which is treated witha mineral acid to effect dehydration of C-5 with concurrent inversion ofthe steric configuration at C-6 thus affording 6a methyl A-pregnen-17ot-ol-3,20-dione. By acylation with a hydrocarbon carboxylicacid anhydride of less than 12 carbon atoms in the presence ofp-toluenesulfonic acid and in benzene solution there is obtained6a-methyl- 17a-acyloxy-9(1l)-dehydro-progesterone (XX) which is in turntreated with chlorine to form 6a-methyl-9u,11fldichloro 17ozacyloxyprogesterone (XXI: Z=saturated linkage). Double bonds may then beintroduced at C1,2 and/ or at C-6,7 as described previously to form 60:-methyl 9a,11,8 dichloro-l7ot-acyloxy-l-dehydro-progesterone (XXI:Z=double bond), 6 methyl 9a,l1l8 dichloro 17cc acyloxy 6dehydro-progesterone (XXII: Z=saturated linkage) and6-methyl-9a,11,8-dichloro-17aacyloxy-1,6-bis-dehydro-progesterone (XXII:Z=double bond).

The following examples serve to illustrate but are not intended to limitthe scope of the invention:

Example I trien-3B-ol-20-one in 800 cc. of methanol was cooled to 15 C.and treated at this temperature with 24 cc. of 4 N sodium hydroxidesolution and 36 cc. of 30% hydrogen peroxide, adding the reagentssimultaneously, little by little and with stirring. The mixture was thenkept at 5 C. overnight, poured into 3,200 cc. of ice water and the solidwas collected by filtration, washed with water, dried and then treatedwith 12 cc. of acetic anhydride and 60 cc. of pyridine, overnight atroom temperature. After pouring into water the mixture was heated forhalf an hour on the steam bath, cooled and the solid was collected,washed with water, dried and recrystallized from methanol, thus givingthe acetate of 16a,17a-oxido-A -pregnadien- 3fi-ol-20-one.

To a stirred solution of 12 g. of the above compound in 140 cc. ofglacial acetic acid was added at room temperature 17.2 cc. of glacialacetic acid saturated with dry hydrogen bromide. After stirring for halfan hour further at room temperature the mixture was poured into waterand the precipitate was collected, and washed with water to neutral.There was thus obtained the 3-acetate of 166- bromo A5901)pregnadiene-3/3,17a-diol-20-one in crude form.

The above bromohydrin, still wet, was refluxed with g. of Raney nickelin 600 cc. of ethanol for 5 hours, at the end of which the hot solutionwas filtered through celite; the filtrate was concentrated under reducedpressure until crystallization started; after cooling the precipitatewas collected by filtration. Recrystallization from acetone furnishedthe 3-acetate of A -pregnadiene-3B, 17at-diol-20-one.

A mixture of 8 g. of the above compound, cc. of acetic acid, 80 cc. ofacetic anhydried and 8 g. of p-tolu-- enesulfonic acid was keptovernight at room temperature and then poured into ice water. Theprecipitate was collected, washed with Water and dried. There was thusobtained the diacetate of A -pregnadiene-3fi,17a-diol- 20-one, which wasused for the next step without further purification.

The above diacetate was dissolved in 400 cc. of 1% methanolic potassiumhydroxide solution and keptfor 4 bonus at 5 C.; it was then acidifiedwith acetic acid, concentrated under reduced pressure to about 40 cc.and diluted with ice water to precipitate the product, namely the17-acetate of A -pregnadiene-3fl,17a-diol-20-0ne, which was purified byrecrystallization from methanol.

To a cooled solution of 3.5 g. of the above compound in 70 cc. ofchloroform was added an ether solution of rnonoperphthalic acidcontaining 1.1 molar equivalents of peracid and the mixture was keptovernight in the dark at 5 C. It was then diluted with water and theorganic layer was separated, washed with saturated aqueous sodiumbicanbonate solution and Water, dried over anhydrous sodium sulfate andthe solvent was evaporated. Chromatography of the residue on neutralalumina afforded the 17-acetate of 5a,6ot oxido-A -pregnene-3,8,17a-diol-20-one.

7 Example 11 To a solution of 2.5 g. of 50,6a-0Xid0-A -pregnene-3fl,17a-diol-20-one-l7-monoaceta-te in 125 cc. of ether and 125 cc. ofbenzene was added 2.5 cc. of recently dis: tilled boron trifluorideetherate and the mixture was kept at room temperature overnight. It wasthen diluted with Water, the organic layer was separated and washedseveral times with water, dried over anhydrous sodium sulfate andevaporated to dryness under reduced pressure. The residue waschromatographed on neutral alumina and the crystalline fractions wererecrystallized from acetonehexane. There was thus obtained the17-acetate of 6/3-fluoro-A -pregnene-3B,5a,17a-triol-20one.

A stirred solution of 2 g. of the above compound in 200 cc. of acetonewas cooled to C., flushed with nitrogen and treated dropw-ise with an 8N solution of chrornic acid, until the color of chromium triox-idepersisted in the mixture. (The 8 N solution of chromic acid had beenprepared by dissolving 26.7 g. of chromium trioxide in 23 cc. ofconcentrated sulfuric acid and dilut-ing with distilled water to 10000.). The mixture was stirred for 5 minutes further at 0 C., thendiluted with ice Water and the precipitate was collected, washed withwater and dried, thus producing the 17-monoacetate of 6 8-fluoro-A-pregnene-5a,17u-diol-3,20-dione.

The above crude product was dissolved in 100 cc. of glacial acetic acidand treated with a stream of dry hydrogen chloride at C. during 2 hours.It was then poured into ice water, the precipitate was collected, washedwith water, dried and recrystallized from acetone ether affording6u-fluoro-9(l1)-dehydro-17aacetoxy progesterone.

A solution of 2 g. of the above compound in 50 cc. of carbontetrachloride was cooled to 5 C. and treated with cc. of a solution ofchlorine in carbon tetrachloride containing 1.05 molar equivalents ofchlorine. The mixture was kept for 2 minutes at 5-10 C., then pouredinto ice water containing 5 g. of sodium carbonate and exhaustivelyextracted with carbon tetrachloride. The extract was washed with waterto neutral, dried over anhydrous sodium sulfate and the solvent wasevaporated; recrystallization of the residue from acetone-hexanefurnished 6a-fluoro-9a-1lfi-dichloro 17u-acetoxyprogesterone.

Example III A mixture of 2 g. of the 17-acetate of 50,6ot-OXidO- A-pregnene-3,B,l7u-diol-20-one and 50 cc. of glacial acetic acid wastreated with a stream of dry hydrogen chloride at 15 C. during 4 hours.The resulting yellow solution was poured into ice water, the precipitatewas collected, washed with water, dried and recrystallized frommethylene chloride-ether thus producing the 17 acetate of 6B-chloro-Apregame-35,50,17a-triol-2O- one, which in turn was oxidized by themethod of the preceding example, to produce the 17-acetate of 65-ch1oro-A -pregnene5u,17a-diol-3,20-dione; after dehydrating by reactionwith dry hydrogen chloride in glacialacetic acid there was obtained6a-chloro-9(11)-dehydro- 17x-acetoxyprogesterone.

1 g. of the above compound was treated with chlorine in carbontetrachloride in accordance with the method described in Example II, togive 6oz,9oc,11fi-tI'lChlOrO-17oc acetoxyprogesterone.

Example IV A mixture of 1 g. of6ot-fluoro-9a,1lfi-dichloro-ljuacetoxyprogesterone, described in ExampleII, 300 mg. of selenium dioxide, 50 cc. of t-butanol and a few drops ofpyridine was refluxed under an atmosphere of nitrogen for 48 hours. Itwas then filtered through celite, the filter was washed with a littlehot ethyl acetate, the filtrate and washings were combined and thesolvent was evaporated under reduced pressure; the residue was purifiedby chromatography on silica gel, thus yielding 6a-fluoro- 904,1lfl-dichloro-l-dehydro-l 7u-acetoxyprogesterone.

Example V In accordance with the dehydrogenation method de scribed inthe previous example, 6oc,9oc,11BtIiChlO1O-17ec acetoxy-progesterone wascoverted into 6u,9oc,11B-trichlorol-dehydro-17a-acetoxy-progesterone.

Example VI A mixture of 3 g. of 6a-methyl-A -pregnadien-17ao=l-3,20-d-ione, described in US. Patent 2,867,633, cc. of glacialacetic acid, 60 cc. of acetic anhydr-ide and 3 g. of p-tol-uenesulfonicacid was kept for 2 hours at room temperature and then poured intowater; the reaction mixture was heated on the steam .bath for half anhour, cooled and the precipitate was collected, washed with water, driedand chromatographed on neutral alumina. There was thus obtained6ot-methy1-A -pregnadien-17a-ol-3,ZO-dione acetate.

By following the chlorination method of Example I, 1 g. of the abovecompound was converted into 6amethyl-9a,1lfi-dichloro A -pregnen17oc-0l-3,20 dione acetate, i.e. 6a-methy-l-9a,11B-dichloro-17a-acetoxyprogesterone. Selenium dioxide oxidation of this compound in accordancewith the method of Example IV, gave 6o-me1;hyl-9or,l1,8-dichloro-Apregnadien17x-ol-3,20- dione acetate.

Example VII A small amount of solvent was distilled from a mixture of 6g. of the 17-acetate of A -pregnadiene-3fl, c-CliOi-20-0I16 (describedin Example I), 420 cc. of toluene and 60 cc. of cyclohexanone until thetraces of moisture were removed by azeotropic distillation. There wasthen added 2.6 g, of aluminum isopropylate dissolved in 40 cc. of drytoluene, in the course of 5 minutes; it was then refluxed for 1 hour atthe end of which the volatile solvents were removed by steamdistillation. After cooling the product was extracted with ether, theextract was successively washed with 1% sulfuric acid, 1% sodiumhydroxide and Water, dried over anhydrous sodium sulfate and evaporated.Crystallization of the residue from acetone-hexane afforded9(l1)-dehydro- 17 a-acetoxypro gesterone.

Example VIII The conversion of the above compound into Qua-1113-dichloro-17a-acetoxyprogester0ne was carried out with the same result bythe following procedures:

(a) A solution of 2 g. of 9(11)-dehydro17a-acetoxyprogesterone in 50 cc.of carbon tetrachloride was cooled to 5 C. and treated with 20 cc. of asolution of chlorine in carbon tetrachloride containing 1.05 molarequivalents of chlorine. The mixture was kept for 2 minutes at 5-10 C.,then poured into ice water containing 5 g. of sodium carbonate andexhaustively extracted with carbon tetrachloride. The extract was washedwith water to neutral, dried over anhydrous sodium sulfate and thesolvent was evaporated; recrystallization of the residue fromacetone-hexane furnished 90,11,8-dichloro-17a-acetoxyprogesterone.

(b) A solution of 2 g. of 9(11)-dehydro-17a-acetoxyprogesterone in 50cc. of methylene chloride was mixed with 1.1 molar equivalents ofN-chlorosuccinimide and cooled to 80 C. A slow stream of dry hydrogenchloride was then introduced into the solution of 80 C. forapproximately 15 minutes, then warmed to 0 C. and kept at thistemperature for 2 hours. The product was then isolated as described inprocedure (a) to produce 911,11 B-dichloro-17a-acetoxyprogesteronehaving identical properties to those of the compound obtained by thatmethod.

Example IX In accordance with the method described in Example I, therewas prepared 3 g. of the 3-acetate of A -pregnadime-36,17a-diol-20-one,which was then refluxed with 28 cc. of ethylene glycol, 270 cc. ofbenzene and 2.3 g.

of p-toluenesulfonic acid monohydrate, for 18 hours and With the use ofa water separator. The solution was then washed with aqueous sodiumcarbonate solution and with water to neutral, dried over anhydroussodium sulfate and the benzene was evaporated. The residue consisted ofthe 3-acetate of 2O-ethylenedioxy-A -pregnadiene-3,B,l7a-diol in crudeform which was then treated with 1.1 molar equivalents ofmonoperphthalic acid, as described in Example I; the crude product waschromatographed on neutral alumina, thus giving the 3-acetate of5a,6a-oxido-20-ethylenedioxy-A -pregnene 35,17- diol.

A mixture of 1.5 g. of the above compound, 55 cc. of anhydrous benzeneand 12.5 cc. of a 3 N ether solution of methyl magnesium bromide wasrefluxed for 6 hours, at the end of which it was poured into a mixtureof 200 cc. of water, 200 g. of ice and g. of ammonium chloride, stirringvigorously. The benzene layer was then separated, washed with dilutehydrochloric acid and water to neutral, dried over anhydrous sodiumsulfate and the solvent was evaporated; the residue was treated with 100cc. of acetone, 2 cc. of Water and 500 mg. of p-toluenesulfonic acid andkept overnight at room temperature. Upon dilution with water, filtrationof the solid and recrystallization from acetone-hexane there wasobtained 6B-methyl-A -pregnene-3,8,5a,17zx-triol-20-one.

Exactly as described in Example II, the SB-hydroxy group was thenoxidized by reaction with 8 N chromic acid and the resulting 65-methyl-A-pregnene-5a-17adiol-3,20-dione was dehydrated to6u-methyl-9(11)-dehydro-l7a-hydroxyprogesterone. There was then appliedthe method of acetylation with acetic anhydride in acetic acid in thepresence of p-toluenesulfonic acid, also as described in Example I.There was thus obtained 6amethyl-9 1 l)-dehydro-17a-acetoxyprogesterone.

1 g. of the above compound was treated with chloride by the method(described in Example VIII, procedure b) to give 6a methyl 9a,1 1Bdichloro-17a-acetoxyprogesterone identical with the product obtained inExample VI.

Example X A mixture of 1 g. of 901,1lB-dichloro-lh-acetoxyprogesterone(Example VIII), 300 mg. of selenium dioxide, 50 cc. of t-butanol and afew drops of pyridine was refluxed under an atmosphere of nitrogen for48 hours. It was then filtered through celite, the filter was washedwith a little hot ethyl acetate, the filtrate and washings were combinedand the solvent was evaporated under reduced pressure; the residue waspurified by chromatography on silica gel, thus yielding 90,11/3-dichloro-l-dehydro-17a-acetoxyprogesterone.

A mixture of 500 mg. of the above compound, 1 g. of chloranil, 7.5 cc.of ethyl acetate and 1 cc. of glacial acetic acid was refluxed under anatmosphere of nitrogen for 55 hours at the end of which there was addedcc. more of ethyl acetate, the mixture was washed with cold 5% sodiumhydroxide solution until the washings were colorless, then with water,dried over anhydrous sodium sulfate and the organic solvent wasevaporated under reduced pressure. The residue was chromatographed onneutral alumina, thus affordinggd,11/3-dichloro-1,6-bis-dehydro-l7u-acetoxyprogesterone.

Example XI There was inverted the order of the dehydrogenationsdescribed in the preceding example; by the reaction with chloranil,there was obtained 9a,l1B-dichloro-6-dehydro- 17et-acetoxyprogesterone;by reaction of the latter with selenium dioxide there was produced9a,11/3-dichl0ro- 1,6-bis-dehydro-l7a-acetoxyprogesterone, identicalwith the final compound of the preceding example.

Example XII By following the methods described in Examples X and XI,6a-fiuoro-9a,1lfi-dichlord17a-acetoxyprogesterone described in ExampleII was converted into6-flu'oro-9u,11fldichloro-6-dehydro-17u-aoetoxyprogesterone.

Example XIII By following the methods described in Examples X and XI,6a,9u,11p-trichloro-l7a-acetoxyprogester0ne of Example III was convertedinto 6u,9a,1lfi-trichloro-l-dehydr-o-17a-acetoxyprogesterone (identicalwith the product of Example V),6,9a,11[i-trichloro-1,6-bisdehydro-17aacetoxyprogesterone and6,9a,1lfl-trichloro-G-dehydro- 17a-acetoxyprogesterone.

Example XIV Example XV By applying the methods of Examples X and XI to60- methyl :,115 dichloro-17a-acetoxyprogesterone there were formed6a-methyl-9a,11,8-dichloro-1-dehydro-17aacetoxyprogesterone,6methyl-9a,1 1B-dichloro-1,6-bisdehydro-17a-acetoxy-progesterone and6-methyl-9a,11 3-dichlor-o-6-dehydro-17a-acetoxyprogester0ne.

Example XVI In accordance with the method described in Example I therewas prepared 3 g. of the 3-acetate of M -pregnadiene-3fl,l7a-diol-20-onewhich was dissolved in cc. of anhydrous benzene, treated with 4 cc. ofpropionic anhydride and 500 mg. of p-toluenesulfonic acid and themixture was kept overnight at room temperature. The benzene solution wasthen washed with 5% aqueous sodium carbonate solution and then withwater, dried over anhydrous sodium sulfate and the solvent wasevaporated There was thus obtained the crude-3-acetate-17-propionate ofA -pregnadiene-3[3,17a-diol-20-one which was next treated withmethanolic potassium hydroxide solution, as

described in Example I, to produce the 17-propionate of A-pregnadiene-3B,l7a-diol-20-one. Upon subsequent Oppenauer oxidationthere was produced the propionate of17ot-hydroxy-9(1l)-dehydroprogesterone, and treatment of the latter withchlorine afforded 90:,1lfi-diChlOI0- 17oc-propionoxyprogesterone.

Example XVII In the method of the preceding example there was employedhexanoic anhydride (6 g.) instead of propionic anhydride, and themixture was allowed to react for 48 hours at room temperature. There wasthus obtained the respective lntermediates having the capronoxy group at17a and finally there was obtained the caproate of 9a, 11,8-dichloro-17u-hydroxyprogesterone.

Example XVIII In accordance with the method of Example II, there wastransformed the 17-propionate of A -pregnadiene- 3,8,17wdiOI-20-One(Example XVI) into the propionate of 60afluoro-9a,11,8-dichloro-17a-hydroxyprogesterone; by appyling the methodof Example III, there was obtained the propionate of 6a,9z,1lfi-trichloro-17a-hydroxyprogesterone; in accordance with the methodof Example XIV there was obtained the propionate of 6a-bromo-9a,11,8-dichloro-17a-hydroxyprogesterone.

1 1 Example XIX In accordance with the method of the preceding example,from the 17-hexanoate of A -pregnadiene-3fi,17adiol--one (Example XVII),there were finally obtained the hexanoates of6ot-fluoro-9u,11B-dichloro-17fl-hydroxyprogesterone, of 60c,9oc,11B-trichloro-17 a-hydroxyprogesterone, and of 6a-brOII10-9oc,11,B-dichloro-l7a-hydroxyprogesterone.

Example XX By applying the esterification described in Examples XVI andXVII to 6ocI1'16thyl-9(11 )-dehydro-17a-hydroxygesterone (Example VI)there were formed its propionate and hexanoate, respectively, and uponsubsequent reaction with chlorine there were obtained the propionatesand hexanoates of 6a-methyl-9a,11fi-dichloro-17a-hydroxyprogesterone.

Example XXI By applying the dehydrogenations described in Examples X andXI to the final compounds of Examples XVI through XX there were preparedthe propionates and hexanoates of the 9a,11B-dich loroderivates of1-dehydro-17ahydroxyprogesterone,6a-fiuoro-1-dehydro-17a-hydroxyprogesterone,6a-chloro-1-dehydro-17ot-hydroxyprogesterone,6a-bromo-l-dehydro-17a-hydroxyprogesterone, 6amethyl1-dehydro-l7oc-hydroxyprogesterone, 6-dehydro- 17a-hydroxyprogesterone,6-fiuoro-6-dehydro-l7a-hydroxyprogesterone,6-chloro-6-dehydro-17ot-hydroxyprogesterone, 6 bromo 6 dehydro 17cchydroxyprogesterone, 6-methyl-6-dehydro-17a-hydroxyprogesterone,1,6-bis-dehydro-17a-hydroxyprogesterone, 6-fluoro-1,6-bis-dehydro- 17ahydroxyprogesterone, 6-chloro-1,6-bis-dehydro-17othydroxyprogesterone, 6bromo-l,6-bis-dehydro-17a-hydroxyprogesterone and6-methyl-1,6-bis-dehydro-17rx-hydroxy-progesterone.

Example XXII A solution of 1 g. of9a,1lfi-dichloro-17a-acetoxy-progesterone in cc. of methanol was treatedwith 175 mg. of potassium hydroxide previously dissolved in 0.2 cc. ofwater and 2.5 cc. of methanol and the mixture was refluxed for 2 hoursunder an atmosphere of nitrogen; it was then neutralized with aceticacid and the solvent evaporated almost to dryness under vacuum. Waterwas added and the formed precipitate collected by filtration, washedwith water and dried. Crystallization from acetone-ether gave the pure912,11/3-dichloro-17a-hydroxyprogesterone.

In a similar manner 6a,9a,1lfl-trichloro-17a-acetoxyprogesterone,6oz-flu01O-9u,1 1,8-dichloro-l7u-acetoxy-1-dehydro-progesterone,6a-methyl-9a,1 l B-dichloro-lh-aceto'xy-progresterone, 90,1 1fi-diChlOl'O-l,G-biSdChYdIO-I'Iuacetoxy-progesterone and6-methyl-6-dehydro-17a-propionoxy-progesterone were converted into thecorresponding free compounds.

I claim:

'1. A compound of the following formula:

wherein X is selected from the group consisting of hydrogen, methyl,fluorine, chlorine and bromine and R is a hydrocarbon carboxylic acylgroup of less than 12 carbon atoms.

2. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 9oc,11,8-dichloro-6-dehydro-l7a-hydroxyprogesterone.

3. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 6-methyl-9a,11fi-dichloro-6-dehydrol7a-hydroxyprogesterone.

4. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 6-flLlOIO-9oc,11fl-diCh101O-6-d6hYdIO- 17a-hydroxyprogesterone.

5. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 6-bromo-9a,l1fl-dichloro-6-dehydro- 17a-hydroxyprogesterone.

6. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 6,9u,1lfi-trichloro-6-dehydro-17x-hydroxyprogesterone.

7. A compound of the following formula:

wherein X is selected from the group consisting of hydrogen, methyl,fluorine, chlorine and bromine and R is a hydrocarbon carboxylic acylgroup of less than 12 carbon atoms.

8. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 9a,1lfl-dichloro-l,6-bisdehydro-17uhydroxy progesterone.

9. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 6-fluoro-9a,11fl-dichloro-1,6-bisdehydro-lh-hydroxy progesterone.

10. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 6-bromo-9a,11/3-dichloro-1,6-bisdehydro-17a-hydroxy progesterone.

11. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 6-methyl-9a,11B-dichloro-1,6-bisdehydro-17a-hydroxy progesterone.

12. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 6,9u,1lfi-trichloro-1,6-bisdehydro- 17 m-hydroxy progesterone.

LEWIS GOTTS, Primary Examiner.

L. H. GASTON, MORRIS LIEBMAN, Examiners.

J.A.C.S., vol. 82, pages 230811

1. A COMPOUND OF THE FOLLOWING FORMULA: